Cancer is the second most common cause of death in the United States, exceeded only by heart disease, accounting for approximately 1 in 4 deaths. In 2015, about 589,430 Americans are expected to die of cancer, almost 1,600 people per day, and there will be an estimated 1,658,370 new cancer cases diagnosed in the U.S. alone. As of Jan. 1, 2014, there were approximately 14.5 million Americans living with cancer, or with a history of cancer (American Cancer Society, Cancer Facts & Figures, 2015). The most prevalent cancer types include prostate cancer, breast cancer, lung cancer and colorectal cancer.
The majority of cancer therapies are severely limited by significant side effects due to non-specific tissue toxicity. The identification and development of therapeutic agents that are selectively toxic to malignant cells is a key goal in cancer research. Many tumors harbor genetic defects that distinguish them from normal cells, and some of these defects have the potential to be exploited in the development of targeted therapies for cancer.
A significant amount of work has focused on applying the specific binding activity of monoclonal antibodies to the development of tumor-specific therapies. Select antibodies such as trastuzumab (HERCEPTIN®), rituximab (RITUXAN®), and cetuximab (ERBITUX®) have received approval for use in human cancer therapy. However, all of these therapeutic antibodies lack the ability to penetrate into cancer cells and are therefore limited to attacking targets located on the external surface of tumor cells, such as growth factors and membrane receptors.
Approximately 30% of all human malignancies are associated with mutations in the Ras family of small GTPase proteins. Amongst the Ras family of GTPases, mutation in the K-Ras gene is most frequently associated with development of cancer. Cells with activating K-Ras mutations are highly associated with specific tumor types, including pancreatic, colorectal, and lung cancers. However, the cell membrane is substantially impermeable to many larger macromolecules, and the intracellular Ras molecule has long been considered an un-drugable target due to its location.
Current approaches to the therapeutic regulation of intracellular targets are largely based on the use of small molecules that are capable of passive diffusion into cells. However, small-molecule inhibitors are prone to causing off-target effects that can result in significant toxicity, and at present there are no highly effective methods of specifically targeting cancer cells harboring mutant K-Ras.
It is therefore an object of the invention to provide agents and methods of use thereof that selectively target cells with aberrant G-protein signaling, particularly those cells that rely on such signaling for proliferation and survival.
It is a further object of the invention to provide agents and methods of use thereof that are selectively cytotoxic to cancer cells and other undesirable cells that possess mutations in the small GTPase K-Ras.